JP6892450B2 - Production of xylene derivatives - Google Patents

Description

The present invention relates to the production of ortho-xylylenediamine, meta-xylylenediamine, and 1,2,3-tri (aminomethyl) benzene from xylene derivatives, particularly furfural and derivatives thereof. The present invention describes a novel pathway for converting furfural and its derivatives into xylene derivatives containing novel intermediates.

In recent years, there has been an increasing tendency to obtain various chemical substances from renewable resources. In this regard, there is a tendency to produce chemicals from biomass carbohydrates such as cellulose, starch, hemicellulose, sugar and the like. Under dehydration conditions, these carbohydrates can be converted to several interesting chemicals, including furfural, hydroxymethylfurfural, and derivatives thereof. There is interest in using these chemicals in the production of value-added chemicals. Examples of such value-added chemical compounds are orthophthalic acid (commonly referred to as phthalic acid), terephthalic acid, isophthalic acid, trimellitic acid, hemmellitic acid, pyromellitic acid, and two or more carboxylic acids. Other benzene derivatives containing acid moiety substituents can be mentioned.

One method for converting furan, furfural, and their derivatives into chemically more valuable 6-membered ring aromatic compounds is the Diels-Alder reaction between the furan ring system and ethylene or ethylene derivatives.

The Diels-Alder reaction with furan derivatives is known. The Diels-Alder reaction of furan and ethylene to 3,6-epoxycyclohexane is described in US Pat. No. 2,405,267.

International Publication No. 2010/151346 describes the conversion of 2,5-dimethylfuran to para-xylene.

A method for the preparation of a substituted benzene derivative by reacting a furfuryl ether with an ethylene derivative is described in International Publication No. 2013/048248 Pamphlet.

WO 2014/06657 widely claims a method for the preparation of benzene derivatives by reacting furan derivatives with ethylene. Furan derivatives can have various substituents at the 2- and 5-positions, including alkyl, aralkyl, -CHO, -CH ₂ OR ³ , -CH (OR ⁴ ) (OR ⁵ ), and -COOR ^6. However, this document provides only examples with dimethyl esters of 2,5-dimethylfuran, 2-methylfuran, 2,5-furandicarboxylic acids, and 2,5-furancarboxylic acids. In particular, there is no example of converting furfural into a benzene derivative.

Green Chem. , 2012, 14, 3314-3325, Yu-Ting Cheng et al. Provide an overview of the formation of target aromatics by using reactions with Diels-Alder class furans and olefins. The authors found that furan, methylfuran, and dimethylfuran react smoothly with olefins, while the first step in furfural conversion is decarbonylation to form furan and CO. The resulting franc then enters a known franc conversion reaction.

These challenges in reacting furfural with olefins are identified in WO 2014/197195. The authors of this document conducted screening experiments in the test range of various solvents, catalysts, reaction temperatures, pressures and times, and 5-hydroxy-2-furfural concentrations, but systems in which 4-hydroxymethylbenzaldehyde was formed. Could not be identified (Example 4.3). The authors have proposed to solve this problem by air oxidation of 5-hydroxymethyl-2-furfural, which produces the corresponding 5-hydroxymethyl-2-fluoroic acid or other oxidized derivative, with olefins. It has been shown to work well in the Diels-Alder reaction.

Both decarbonylation of furfural to furan and oxidation of furfural to furoic acid have the disadvantage of losing the aldehyde substituent on the furan ring. As a result, aldehyde substituents are no longer present in the resulting Diels-Alder adduct, which makes it more difficult to obtain benzaldehyde derivatives from furan derivatives, especially furfural. However, benzaldehyde derivatives are desirable as valuable intermediates in the preparation of other important chemical compounds such as meta-xylylenediamine, ortho-xylenediamine, and 1,2,3-tri (aminomethyl) benzene.

In order to solve the above-mentioned problems, the present inventors have conducted various experiments in an effort to react furfural with an ethylene derivative. As expected from prior art, the reaction between furfural and acrylonitrile was not observed even under various conditions with respect to catalyst, molar ratio of reactants, temperature and reaction time. We then converted the aldehyde substituent of furfural to its diethyl-ketal. Ketal is a known derivative of an aldehyde from which the desired aldehyde can be easily obtained by removing the alcohol. However, when furfural diethyl-ketal was reacted with acrylonitrile, a slight trace of Diels-Alder adduct, oxanorbornene, was observed. Upon further examination, we have found that the furfural cyclic ketal surprisingly reacts with acrylonitrile, thereby forming the desired Diels-Alder adduct. In a further reaction step, the cyclic ketal is converted back to the desired aldehyde substituent, which can be further reacted with other substituents if desired. This finding is particularly surprising given that furfural dialkyl-ketal derivatives do not form Diels-Alder adducts with ethylene derivatives.

During the study, we further found that furfural cyclic ketals surprisingly react only with certain ethylene derivatives. For example, it was found that furfural cyclic ketals do not react with allylamine and acrylamide. In the Diels-Alder condensation reaction, only acrylonitrile and fumaronitrile reacted smoothly.

（式中、
Ｘ及びＹは、独立して、任意選択的に置換されるヘテロ原子であり、
Ｒは、１つ以上のＲ^１で任意選択的に置換され得るＣ_１〜４アルキレン基であり、
Ｒ^１は、任意選択的に１つ以上の官能基を有する直鎖型、分岐型、及び／又は環式の飽和又は不飽和の炭化水素基であり、
Ｒ^２は、独立して、Ｈ、アルキル、アルケニル、又はアリールであり、
Ｒ^３及びＲ^４は、独立してＨ又は−ＣＮであり、但し、Ｒ^３及びＲ^４の少なくとも１つは、−ＣＮであり、
Ｒ^５は、Ｒ^２、−ＣＨ_２ＯＲ^２、−ＣＯ_２Ｒ^２、又は

である）の化合物の調製のための方法に関し、これは、式（ＩＩ）

（式中、Ｘ、Ｙ、Ｒ、Ｒ^２及びＲ^５は、前述の通り定義される）の化合物を、式（ＩＩＩ）又は（ＩＩＩ’）

（式中、Ｒ^３及びＲ^４は、前述の通り定義される）の化合物と反応させることを含む。 Therefore, the present invention has the formula (I).

(During the ceremony
X and Y are heteroatoms that are independently and optionally substituted.
R is one or more _{C 1 to 4} alkylene group which may be optionally substituted with ^{R 1,}
R ¹ is a linear, branched, and / or cyclic saturated or unsaturated hydrocarbon group optionally having one or more functional groups.
R ² is independently H, alkyl, alkenyl, or aryl,
R ³ and R ⁴ are independently H or -CN, except that at least one of ^{R 3} and R ^{4 is -CN.}
R ⁵ is R ² , -CH ₂ OR ² , -CO ₂ R ² , or

With respect to the method for the preparation of the compound of formula (II).

Compounds of the formula (where X, Y, R, R ² and R ⁵ are defined as described above) are compounded in formula (III) or (III').

In the formula, R ³ and R ⁴ include reacting with a compound (as defined above).

The furan derivative of formula (II) used as a starting material can be obtained from biomass resources. For example, furan derivatives can be derived from the dehydration of carbohydrates. Carbohydrates are appropriately selected from polysaccharides, oligosaccharides, disaccharides, and monosaccharides. Suitable biomass sources and suitable methods for their conversion to furfural derivatives are known to those of skill in the art. Alternatively, the furfural derivative can be a commercially available chemical product obtained by a conventional chemical reaction.

In the furfural derivative of formula (II), the aldehyde residue of furfural exists as a cyclic ketal. However, the present invention is not limited to furfural and its cyclic ketal derivative, and further includes a furan derivative containing a heteroatom other than O. Therefore, X and Y in the compound of formula (II) are independent of each other and consist of optionally substituted heteroatoms such as O, S, and N. In this regard, "optionally substituted" defines that a heteroatom can have a substituent if desired. If the heteroatom cannot have any additional substituents, then no substituents are present. For example, if the heteroatom is O or S, there are no substituents on the heteroatom. However, if the heteroatom is N, then X and Y can be -NH- or -N (substituent)-. The substituents have the same meaning as R ^1. Therefore, X and Y are preferably ^{selected independently of -O-, -S-, -NH-, and -N (R 1} )-, more preferably -O- and -S-. Most preferably, X and Y are both O or both S.

In the furfural derivative of formula (II), R is a C _1-4 alkylene group, preferably a C _2-4 alkylene group, more preferably a C _2-3 alkylene group, and most preferably a C ₂ alkylene group. The alkylene group may be optionally substituted with one or more R ¹ substituents. R ¹ is a linear, branched, and / or cyclic saturated or unsaturated hydrocarbon group optionally having one or more functional groups. Such hydrocarbon groups include all chemical sites containing carbon atoms, preferably 1 to 24 carbon atoms, in addition to the required number of hydrogen atoms. Examples of linear, branched, and / or cyclic saturated or unsaturated hydrocarbon groups are alkyl, alkenyl, alkynyl, aromatic groups and the like. The hydrocarbon group can optionally have one or more functional groups, wherein the hydrocarbon group is one or more heteroatoms such as O, N, and S, or -CO- or-. It means that it can contain functional groups such as COO-. Further, the hydrocarbon group can be substituted with a functional group such as nitro, nitroso, sulfo, sulfonate, cyano, cyanato, thiosianato, amino, hydroxyl, carboxyl and the like.

Here, to describe the typical examples of R ¹ in greater detail, whereby further, unless otherwise defined, throughout the specification, in particular also the definition of applicable specific terms to all other substituents provide.

As used herein, the term "alkyl" typically refers to necessarily 1 to about 24 carbon atoms, preferably 1 to about 12 carbon atoms, or 1 to about 6 carbon atoms, 1 It does not necessarily contain about 3 carbon atoms, but means a linear, branched, or cyclically saturated hydrocarbon group. Certain embodiments provide that the alkyl is a cycloalkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, octyl, decyl and the like, and cyclopentyl, cyclohexyl and the like. .. In general, again, but not necessarily, in the present specification, an alkyl group contains 1 to about 12 carbon atoms. The term "lower alkyl" is intended for an alkyl group of 1 to 6 carbon atoms, and the particular term "cycloalkyl" typically has 4 to 8 carbon atoms, preferably 5 to 7 carbon atoms. Intended for cyclic alkyl groups. The term "substituted alkyl" means an alkyl group substituted with one or more substituents and includes "heteroatom-containing alkyl" and "heteroalkyl", these terms having at least one carbon atom hetero. Means an alkyl group replaced by an atom. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl and lower alkyl groups, respectively.

As used herein, the term "alkylene" means a bifunctional linear, branched, or cyclic alkyl group, where "alkyl" is as defined above. Is.

As used herein, the term "alkenyl" refers to at least one double, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, etc. It means a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing a bond. Preferred alkenyl groups herein contain from 2 to about 12 carbon atoms. The term "lower alkenyl" is intended for an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" is intended for a cyclic alkenyl group preferably having 5 to 8 carbon atoms. The term "substituted alkenyl" means an alkenyl group substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" have at least one carbon atom substituted with a heteroatom. Means an alkenyl group. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and / lower alkenyl groups, respectively. ..

As used herein, the term "alkenylene" means a bifunctional linear, branched, or cyclic alkenyl group, where "alkenyl" is as defined above. Is.

As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, etc. Means. Preferred alkynyl groups herein contain from 2 to about 12 carbon atoms. The term "lower alkynyl" is intended for an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" means an alkynyl group substituted with one or more substituents, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" have at least one carbon atom substituted with a heteroatom. Means alkynyl. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl groups, respectively.

As used herein, the term "alkoxy" is intended for an alkyl group attached via a single terminal ether bond, i.e. the "alkoxy" group is as alkyl defined above. It can be expressed as a certain -O-alkyl. The "lower alkoxy" group is intended an alkoxy group containing 1 to 6 carbon atoms. Similarly, "alkenyloxy" and "lower alkenyloxy" mean alkenyl and lower alkenyl groups linked via a single terminal ether bond, respectively, and "alkynyloxy" and "lower alkynyloxy" respectively. Means alkynyl and lower alkynyl groups attached via a single terminal ether bond.

The term "aromatic" means a ring moiety that satisfies Hückel's rule 4n + 2 for aromaticity and is an aryl (ie, carbon) comprising an aryl, aralkyl, alkaline, heteroaryl, heteroaralkyl, or alk-heteroaryl moiety. Includes both ring) and heteroaryl (also referred to as heteroaromatic) structures.

As used herein, the term "aryl" is a single aromatic ring that is fused together, directly or indirectly, unless otherwise specified. Alternatively, it means an aromatic substituent or structure containing multiple aromatic rings (so that different aromatic rings are attached by a common group such as a methylene or ethylene moiety). Unless otherwise modified, the term "aryl" means carbocyclic structure. Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms. Typical aryl groups include one aromatic ring or two fused or bonded aromatic rings, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone and the like. "Substituted aryl" means an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" are aryls in which at least one carbon atom is substituted with a heteroatom. It means a substituent and is described in more detail below.

As used herein, the term "aryloxy" means an aryl group attached via a single terminal ether bond, in which case "aryl" is as defined above. The "aryloxy" group can be represented as -O-aryl, in which case the aryl is as defined above. Preferred aryloxy groups contain 5 to 24 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups include, but are not limited to, phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, Examples thereof include 2,4-dimethoxyphenoxy and 3,4,5-trimethoxy-phenoxy.

The term "alkali" means an aryl group having an alkyl substituent, the term "aralkyl" means an alkyl group having an aryl substituent, in which case "aryl" and "alkyl" are mentioned above. As defined in. Preferred alkaline and aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred alkaline and aralkyl groups contain 6 to 16 carbon atoms. Examples of the alkaline group include p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene and the like. Can be mentioned. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenyl. Cyclohexylmethyl, 4-benzylcyclohexylmethyl and the like can be mentioned. The terms "alkalineroxy" and "aralkyloxy" mean substituents of formula-OR, where R is alkaluryl or aralkyl defined immediately before, respectively.

The term "acyl" means a substituent having the formula- (CO) -alkyl,-(CO) -aryl, or-(CO) -aralkyl, and the term "acyloxy" is the formula -O (CO). Means a substituent having an -alkyl, -O (CO) -aryl, or -O (CO) -aralkyl, in which case "alkyl," "aryl," and "aralkyl" are as defined above. ..

The terms "cyclic" and "ring" may or may not be substituted and / or may or may not contain heteroatoms, and may be monocyclic, bicyclic, or polycyclic. It means an alicyclic group or an aromatic group which may be. The term "alicyclic" is used in the conventional sense to mean an aliphatic cyclic moiety as opposed to an aromatic cyclic moiety and can be monocyclic, bicyclic or polycyclic. .. The term "acyclic" means a structure that does not contain a double bond within the ring structure.

The terms "halo" and "halogen" are used in the conventional sense to mean chloro, bromo, fluoro, or iodo substituents.

The term "heteroatom-containing" in "heteroatom-containing groups" and the like refers to atoms in which one or more carbon atoms are other than carbon, such as nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen, or. Means a hydrocarbon molecule or molecular fragment that is replaced by sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent containing a heteroatom, and the term "heterocyclic" means a cyclic substituent containing a heteroatom, "heteroaryl" and "heteroaryl". The term "heteroaromatic" means "aryl" and "aromatic" substituents containing heteroatoms, respectively. The "heterocyclic" group or compound may or may not be aromatic, and the "heterocycle" is monocyclic, bicyclic, or polycyclic as described above with respect to the term "aryl". Note that it can be an expression. Examples of heteroalkyl groups include alkoxyaryls, alkylsulfanil-substituted alkyls, N-alkylated aminoalkyls and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl and the like, and examples of heteroatom-containing alicyclic groups include pyrrolidino. , Morphorino, piperazino, piperidino and the like.

A "substitution" in "substituted alkyl", "substituted aryl", etc., as suggested by some of the above definitions, is attached to a carbon (or other) atom at an alkyl, aryl, or other site. It means that at least one hydrogen atom has been replaced by one or more non-hydrogen substituents. Examples of such substituents are, but are not limited to, halo, hydroxyl, sulfhydryl, C _{1 to} C ₂₄ alkoxy, C _{2 to} C ₂₄ alkenyloxy, C _{2 to} C ₂₄ alkynyloxy, C _{5 to} C ₂₄ aryloxy. , C _{6 to} C ₂₄ aralkyloxy, C _{6 to} C ₂₄ alkaliloxy, acyl (C _{1 to} C ₂₄ alkylcarbonyl (-CO-alkyl), and C _{6 to} C ₂₄ arylcarbonyl (-CO-aryl)) ), including acyloxy (-O- _acyl, C 2 _{-C 24} alkylcarbonyloxy (-O-CO- alkyl), and _C 6 _{-C 24} arylcarbonyloxy (-O-CO- _{aryl)), C} 2 ~ C ₂₄ alkoxycarbonyl ((CO) -O-alkyl), C _{6 to} C ₂₄ aryloxycarbonyl (-(CO) -O-aryl), halocarbonyl (-CO) -X (in the formula, X is halo) ), C _{2 to} C ₂₄ alkylcarbonato (-O- (CO) -O-alkyl), C _{6 to} C ₂₄ arylcarbonato (-O- (CO) -O-aryl), carboxy (-COOH), Carboxylate (-COO-), carbamoyl (-(CO) NH ₂ ), mono- (C _1- C ₂₄ alkyl) -substituted carbamoyl (-(CO) NH (C _1- C ₂₄ alkyl)), di- ( C _{1 to} C ₂₄ alkyl) -substituted carbamoyl (-(CO) -N (C _{1 to} C ₂₄ alkyl) ₂ ), mono- (C _{1 to} C ₂₄ haloalkyl) -substituted carbamoyl (-(CO) -NH (C) _{1 to} C ₂₄ alkyl)), di- (C _{1 to} C ₂₄ haloalkyl) -substituted carbamoyl (-(CO) -N (C _{1 to} C ₂₄ alkyl) ₂ ), mono- (C _{5 to} C ₂₄ aryl)- Substituted carbamoyl (-(CO) -NH-aaryl), di- (C _{5 to} C ₂₄ aryl) Substituted carbamoyl (-(CO) -N (C _{5 to} C ₂₄ aryl) ₂ ), di-N- (C) _{1 to} C ₂₄ alkyl), N- (C _{5 to} C ₂₄ aryl) -substituted carbamoyl, thiocarbamoyl- (C ₅ ) -NH ₂ ), mono- (C _{1 to} C ₂₄ alkyl) -substituted thiocarbamoyl (-( CO) -NH (C _{1 to} C ₂₄ alkyl)), di- (C _{1 to} C ₂₄ alkyl) -substituted thiocarbamoyl (-(CO) -N (C _{1 to} C _{2) 4} Alkyl) ₂ ), mono- (C _{5 to} C ₂₄ aryl) substituted thiocarbamoyl (-(CO) -NHaryl 1), di- (C _{5 to} C ₂₄ aryl) -substituted thiocarbamoyl 1 ((CO)- N (C _{5 to} C ₂₄ aryl) z), di-N- (C _{1 to} C ₂₄ alkyl), N- (C _{5 to} C ₂₄ aryl) -substituted thiocarbamoyl, carbamide (-NH- (CO) -NH2 ), Cyan (-C = N), cyanato (-OC = N), thiocyanato (-SC = N), formyl (-(CO) -H), thioformyl (-(CS) -H), amino _(-NH 2), mono- _- (C 1 _{-C 24} alkyl) - substituted amino, di _- (C 1 _{-C 24} alkyl) - substituted amino, mono _- (C 5 _{-C 24} aryl) - substituted amino, di -(C _{5 to} C ₂₄ aryl) -substituted amino, C _{1 to} C ₂₄ alkylamide (-NH- (CO) -alkyl), C _{6 to} C ₂₄ arylamide (-NH- (CO) -aryl), imino (during -CR = NH (wherein, R = _hydrogen, C 1 _{-C 24 alkyl,} C 5 _{-C 24 aryl,} C 6 _{-C 24 alkaryl,} C 6 _{-C 24} aralkyl, _{etc.), C} 2 ~C ₂₀ alkyl Imino (CR = N (alkyl), in formula, R = hydrogen, C _{1 to} C ₂₄ alkyl, C _{5 to} C ₂₄ aryl, C _{6 to} C ₂₄ alkaline, C _{6 to} C ₂₄ aralkyl, etc.), aryl imino ( -CR = N (aryl), in formula, R = hydrogen, C _{1 to} C ₂₀ alkyl, C _{5 to} C ₂₄ aryl, C _{6 to} C ₂₄ alkalil, C _{6 to} C ₂₄ aralkyl, etc.), nitro (-NO) ₂ ), Nitroso (-NO), Sulfo (-SO ₂ OH), Ssulfonate (SO ₂ O-), C _1-2 C ₂₄ Alkyl sulfanyl (-S-alkyl, also referred to as "alkylthio") C _{5 to} C ₂₄ arylsulfanyl (-S- aryl, also referred to as _"arylthio"), C 1 _{-C 24} alkylsulfinyl (- (SO) - _alkyl), C 5 _{-C 24} arylsulfinyl (- (SO) - aryl), C _{1 to} C ₂₄ alkylsulfonyl (-SO ₂ alkyl), C _{1 to} C ₂₄ monoalkylaminosulfonyl-SO _2- N (H) alkyl), C _{1 to} C ₂₄ dialkylaminosulfonyl-SO _2- N (alkyl) ₂ , C _{5 to} C ₂₄ arylsulfonyl (-SO ₂ -aryl), Boryl (-BH ₂ ), Borono (B (OH) ₂ ), Boronato (-B (OR) ₂ (in the formula, R is an alkyl or aryl)) , Phosphono (-P (O) (OH) ₂ ), phosphonato (P (O) (O) ₂ ), phosphinato (P (O) (O-)), phospho (-PO ₂ ), and phosphine (-PH). ₂ ), and sites C _{1 to} C ₂₄ alkyl (preferably C _{1 to} C ₁₂ alkyl, more preferably C _{1 to} C ₆ alkyl), C _{2 to} C ₂₄ alkenyl (preferably C ₂ C ₁₂ alkenyl, more preferably C 2 C 12 alkenyl). C _{2 to} C ₆ alkynyl), C _{2 to} C ₂₄ alkynyl (preferably C _{2 to} C ₁₂ alkynyl, more preferably C _{2 to} C ₆ alkynyl), C _{5 to} C ₂₄ aryl (preferably C _{5 to} C ₂₄ aryl). ), C _{6 to} C ₂₄ Alkyne (preferably C _{6 to} C ₁₆ Alkyne), and C _{6 to} C ₂₄ Arylkyne (preferably C _{6 to} C ₁₆ Arylkyne).

If a substituent is described as "substituted" or "optionally substituted", those Fn substitutions, preferably, halo, hydroxyl, C ₁ -C ₃ alkoxy, C ₁ -C ₆ alkyl carbonyl (CO- _alkyl), C 2 _{-C 24} alkoxycarbonyl ((CO) -O- alkyl), carboxy (-COOH), carbamoyl _{(- (CO) -NH 2)} , mono- - _(C 1 ~C ₆ alkyl ) -Substituted carbamoyl (-(CO) NH (C _{1 to} C ₆ alkyl)), di- (C _{1 to} C ₆ alkyl) -substituted carbamoyl (-(CO) -N (C _{1 to} C ₆ alkyl) ₂ ) , Cyano (-C = N), cyanate (-OC = N), thiocyanate (-SC = N), formyl (-(CO) -H), amino (-NH ₂ ), mono- (C) _{Includes 1-} C ₆ alkyl) -substituted amino, or di- (C _1- C ₆ alkyl) -substituted amino.

"Functionalization" in "functionalized alkyl", "functionalized olefin", "functionalized cyclic olefin", etc. means a carbon (or other) atom at an alkyl, olefin, cyclic olefin, or other moiety. It means that at least one hydrogen atom bonded to is replaced with one or more functional groups such as those described here and above. The term "functional group" is meant to include any functional species suitable for use as described herein. In particular, as used herein, a functional group will necessarily have the ability to react or bind to the corresponding functional group on the surface of the substrate.

In addition, the functional groups described above may be further substituted with one or more additional functional groups, such as those specifically listed above, where the particular group allows. Similarly, the aforementioned groups can be further substituted with one or more additional functional groups, such as those specifically listed.

_{In a preferred embodiment of the invention, R is C 2} or C ₃ unsubstituted or substituted with one or two, preferably two lower alkyl, preferably methyl or ethyl, more preferably methyl. It is an alkylene group. Preferred examples of _{R, -CH 2 -CH 2 -, -} CH 2 -CH 2 -CH 2 -, - CH (CH 3) -CH (CH 3) -, and _-CH 2 -C _{(CH 3) 2} -CH _2- .

In furfural derivatives of formula (II), R ² is, independently, as previously defined, H, alkyl, alkenyl, or aryl. Preferably, R ² is independently H or alkyl, more preferably H or C _1-4 alkyl, more preferably H or C _1-3 alkyl, even more preferably H or C _1-2 alkyl. , Most preferably H or methyl. In a more preferred embodiment, R ² is H.

（式中、Ｘ、Ｙ、及びＲ、並びにその好ましい実施形態は、前述で定義された通りである）である。 In the furfural derivative of formula (II), R ⁵ is R ² , -CH ₂ OR ² , -CO ₂ R ² , or

(In the formula, X, Y, and R, and preferred embodiments thereof, are as defined above).

Preferably, R ⁵ is R ² , -CH ₂ OR ² , or -CO ₂ R ² , where R ² is H or alkyl, and alkyl is preferably C _1-4 alkyl, especially C 1-4 alkyl. It is methyl or ethyl.

（式中、Ｒ^５’は、Ｈ、メチル、−ＣＨ_２ＯＲ^２’、−ＣＯ_２Ｒ^２’、又は

であり、
Ｒ^２’は、Ｈ又はアルキル、好ましくはＨ又はＣ_１〜４アルキルであり、
Ｘ’及びＹ’は、ともにＯ又はＳであり、
Ｒ’は、１つ又は２つのＣ_１〜４アルキル（好ましくはメチル）で任意選択的に置換されたＣ_２又はＣ_３アルキレンである）、

（式中、Ｒ^５’は、前述の通り定義される）、

（式中、Ｒ^５’は、前述の通り定義される）、

（式中、Ｒ^５’は、前述の通り定義される）、

（式中、Ｒ^５’は、前述の通り定義される）。 Specific embodiments of furfural derivatives of formula (II) are the following compounds:

(Wherein, R ^{5 'is,} H, _{^{methyl, -CH 2 OR 2', -CO}} 2 R 2 ', or

And
R ^2'is H or alkyl, preferably H or C _1-4 alkyl.
Both X'and Y'are O or S,
_{R'is a C 2} or C ₃ alkylene optionally substituted with one or two C 1-4 alkyl (preferably methyl)),

(Wherein, R ^{5 'is} as hereinbefore defined),

(Wherein, R ^{5 'is} as hereinbefore defined),

(Wherein, R ^{5 'is} as hereinbefore defined),

(Wherein, R ^{5 'is} as hereinbefore defined).

The furfural derivative of formula (II) can be obtained, for example, by reacting furfural with ethylene glycol, substituted ethylene glycol, or any other suitable dialcohol. Also, this reaction constituting the protection of the aldehyde functional group of furfural in the form of cyclic ketal is known to those of skill in the art. The protecting reaction can be carried out in a suitable organic solvent such as cyclohexane with a suitable catalyst such as A70 amberlist resin. For example, the furfural derivative of formula (II) of 1,3-dioxolane-2- (2-furanyl) can be obtained quantitatively by reacting furfural with ethylene glycol.

According to the present invention, furfural itself and the dialkyl-Ketal derivative of furfural do not form a Diels-Alder adduct with ethylene and its derivatives, whereas the furfural derivative of formula (II) surprisingly reacts with dienophile. It was found that a Diels-Alder adduct of formula (I) was produced. Therefore, the present invention provides a method for reacting a furfural derivative of formula (II) with an ethylene derivative of formula (III), thereby obtaining a Diels-Alder condensation adduct of formula (I).

The ethylene derivative of formula (III) or (III') has two substituents R ³ and R ⁴ . These substituents are independently H or -CN, except that at least one of ^{R 3} and R ^{4 is -CN.} Therefore, the ethylene derivative of formula (III) or (III') has at least one substituent. In one embodiment, R ⁴ is H and R ³ is -CN. Alternatively, ^{both R 3} and R ⁴ can be -CN. If both R ³ and R ⁴ are -CN, the ethylene derivative comprises the cis and trans isomers of fumaronitrile.

The Diels-Alder condensation reaction between the compound of formula (II) and the compound of formula (III) or (III') can be carried out under the usual Diels-Alder conditions known to those skilled in the art. Depending on the particular derivative used, the condensation reaction can be carried out in the presence or absence of any catalyst and with or without any solvent. The reaction takes a sufficient amount of time to convert the starting compound to the desired Diels-Alder adduct, eg, about 2 or 5 seconds to about 6 days, preferably about 3 hours to about 4 days, more preferably about 12 hours. It can be carried out in about 4 days, for example, about 24 hours, at any suitable temperature of about 10 to about 120 ° C., preferably about 20 to about 100 ° C., more preferably about 20 to about 80 ° C. The reaction can be carried out by increasing the ambient pressure or pressure. Advantageously, the reaction is carried out at an ambient pressure, eg, up to about 1000 hPa, or about 10000 hPa, preferably up to about 5000 hPa, more preferably up to about 2000 hPa.

Advantageously, the Diels-Alder reaction is carried out in the presence of a catalyst, particularly a known Diels-Alder catalyst. These catalysts include Lewis acids such as aluminum, boron, zinc, hafnium, or iron compounds such as AlCl ₃ , Al (Et) Cl ₂ , Al (Et) ₂ Cl, BF ₃ , B (Ac) ₃ , ZnCl ₂ , ZnBr ₂ , Zn (Ac) ₂ , ZnI ₂ , CuCl ₂ , Sc (OTf) ₃ , Bi (OTf) ₃ , and BiCl ₃ , FeCl ₃ , Fe (Ac) ₃ , FeCl ₂ , and Fe ( Ac) ₂ , Bronsted acids such as inorganic mineral acids such as sulfuric acid, phosphoric acid, nitrate, hydrobromic acid or hydrochloric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, or carboxylic acid. Can be mentioned. Examples of Diels-Alder catalysts include halides of tin or titanium, such as SnCl ₄ and TiCl ₄ . Alternatively, activated carbon, silica, alumina, silica-alumina, zirconia, or zeolite can be used. Carbon, silica, alumina, silica-alumina, zirconia, and zeolite can be used as is, but can also be used as a carrier for catalytically active metals or metal compounds. Appropriate examples of such metals or metal compounds include alkali metals, alkaline earth metals, transition metals, noble metals, and rare earth metals. For example, the catalyst can be acidic by treating the carrier with phosphoric acid or by ion exchange of zeolite to its acid form. The catalyst can be an acid catalyst. Examples of solid catalysts include amorphous silica-alumina, zeolites, preferably zeolites in H-form thereof, and acidic ion exchange resins. Other suitable catalysts that are liquid or can be dissolved in a suitable solvent to produce a uniform catalytic environment include alkane carboxylic acid, arene carboxylic acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, and nitric acid. Organic and inorganic acids such as.

A Diels-Alder condensation reaction between a compound of formula (II) and a compound of formula (III) or (III') yields an oxanorbornene derivative of formula (I). Depending on the starting compound used, the resulting oxanorbornene can be obtained as different isomers. All possible isomers are included within the scope of the present invention.

For example, if the compound of formula (II) ^{reacts with acrylonitrile (a compound of formula (III) where one of R 3} and R ⁴ is H and the other is -CN), the resulting oxanorbornene derivative is ortho. It can be an isomer, a meta-isomer, or a mixture of both. In other words, the oxanorbornene derivative can have a -CN substituent resulting from the compound of formula (III) at the ortho or meta position with respect to the protected aldehyde substituent. In addition, both the meta-isomer and the ortho-isomer can exist as endo- or exo-isomers. Also, these potential isomers are included within the scope of the present invention.

The present inventors have found that various isomers can be distinguished from each other by NMR displacement measurement. This is the Diels-Alder condensation formation between 1,3-dioxolane-2- (2-furanyl) (compound of formula (II)) and acrylonitrile (compound of formula (III)) in Example 1.2. It is indicated by four possible isomers obtained as a compound.

The various isomers can exist as a mixture of two or more isomers or in the form of a single isomer.

Even more surprisingly, when a furfural derivative of formula (II) (wherein X and Y are both O) is reacted with a compound of formula (III) or (III'), oxanorbornene of formula (I) is reacted. It has been found to produce approximately equal amounts of ortho- and meta-isomers of the derivative. However, if both X and Y in the compound of formula (II) are S, the reaction produces 100% ortho-isomers of the oxanorbornene derivative of formula (I). Therefore, by selecting X and Y in the starting compound of the formula (II), the desired oxanorbornene isomer obtained by the Diels-Alder condensation reaction can be selected.

The oxanorbornene derivative of formula (I) constitutes an intermediate useful in the preparation of other chemical compounds such as 2- or 3-cyanobenzaldehyde, or 2,3-dicyanobenzaldehyde, which in turn then comprises the following reaction: Depending on the scheme, it can be converted to ortho-xylene diamine, meta-xylene diamine (MXD), or 1,2,3-tri (aminomethyl) benzene (a preferred example of the method according to the invention is shown).

Aromatization and deprotection of the compound of formula (I) can be carried out in the single step described above. Alternatively, the desired compound of formula (IV) can be obtained in a two-step process via an intermediate of formula (V). This alternative route is shown in the reaction scheme below, which again illustrates the reaction with the preferred compounds.

（式中、
Ｘは、任意選択的に置換されるヘテロ原子であり、
Ｒ^２は、独立して、Ｈ、アルキル、アルケニル、又はアリールであり、
Ｒ^３及びＲ^４は、独立して、Ｈ又は−ＣＮであり、但し、Ｒ^３及びＲ^４の少なくとも１つは、−ＣＮであり、及び
Ｒ^５は、Ｒ^２、−ＣＨ_２ＯＲ^２、又は−ＣＯ_２Ｒ^２、又は

であり、
式中、Ｙは、任意選択的に置換されるヘテロ原子であり、
Ｒは、１つ以上のＲ^１で任意選択的に置換され得るＣ_１〜４アルキレン基であり、及び
Ｒ^１は、１つ以上の官能基を任意選択的に有する直鎖型又は分枝型の飽和又は不飽和の炭化水素基である）の化合物の調製のための方法に関し、これは、
ａ）式（Ｉ）

（式中、Ｘ、Ｙ、Ｒ、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は、前述の通り定義される）の化合物を脱水／芳香族化して、式（Ｖ）

（式中、Ｘ、Ｙ、Ｒ、Ｒ^２、Ｒ^３、Ｒ^４、及びＲ^５は、前述の通り定義される）の化合物を得、次いで式（Ｖ）の化合物を脱保護すること、又は
ｂ）単一の工程で式（Ｉ）の化合物の脱水／芳香族化及び脱保護を行うこと
を含む。 Therefore, the present invention also describes the formula (IV).

(During the ceremony
X is a heteroatom that is optionally substituted and
R ² is independently H, alkyl, alkenyl, or aryl,
R ³ and R ⁴ are independently H or -CN, except that ^{at least one of R 3} and R ⁴ is -CN, and R ⁵ is R ² , -CH ₂ OR ² , Or -CO ₂ R ² , or

And
In the formula, Y is a heteroatom that is optionally substituted.
R is one or more C _{1 to 4} alkylene group which may be optionally substituted with R ^1, and R ¹ is linear or branched having one or more functional groups optionally With respect to the method for the preparation of compounds (which are saturated or unsaturated hydrocarbon groups), this is
a) Equation (I)

Compounds of (in the formula, X, Y, R, R ² , R ³ , R ⁴ and R ⁵ are defined as described above) are dehydrated / aromaticized to formula (V).

^{(Wherein, X, Y, R, R} 2, R 3, R 4, and ^{R 5} are as described above is defined) to give a compound of the then deprotecting the compound of formula (V), or b) Including dehydration / aromatization and deprotection of the compound of formula (I) in a single step.

The reaction conditions for aromatization and deprotection of the compound of formula (I) are well known to those skilled in the art. However, surprisingly, the aromatization reaction of the compound of formula (I) requires basic reaction conditions, for example, in the presence of methoxide or hydroxide, such as sodium methoxide or sodium hydroxide. There was found. For example, the aromatization reaction can be carried out in quantitative yield using sodium methoxide dissolved in DMSO at a temperature of 100 ° C. for about 1 hour. Alcohols, such as methanol and ethanol, are other suitable solvents.

Preferably, the compound of formula (I) is obtained by the method described above using furfural, particularly a cyclic ketal derivative of furfural having formula (II), as a starting material.

の化合物である。 If desired, the compound of formula (IV) obtained by the method described above can be, for example, meta-xylylenediamine, ortho-xylenediamine, or other chemistry such as 1,2,3-tri (aminomethyl) benzene. It can be further converted to a compound. If meta-xylylenediamine is the desired final product, the compound of formula (IV) is preferably 3-cyanobenzaldehyde, formula (VII').

It is a compound of.

Meta-xylylenediamine can be obtained from 3-cyanobenzaldehyde by hydrogenation of the cyano site and reductive amination of the aldehyde site. Nitrile hydrogenation and reductive amination are performed, for example, with 3-cyanobenzaldehyde (NH ₃ / 3-cyanobenzaldehyde ratio _{) in NH 3} solution dissolved in methanol at 100 ° C., 50 bar hydrogen, using Co Laney as a catalyst. By reacting about 19), it can be carried out at the same time. Alternatively, nitrile hydrogenation and reductive amination can be subsequently performed as shown in the reaction scheme below.

Similarly, ortho-xylene diamine and 1,2,3-tri (aminomethyl) benzene can be obtained.

（式中、Ｒ^６は、独立して、Ｈ、又は−ＣＨ_２−ＮＨ_２であり、但し、Ｒ^６の少なくとも１つは、−ＣＨ_２−ＮＨ_２である）のキシレン誘導体の調製のための方法に関し、これは、
式（ＶＩＩ）

（式中、Ｒ^７は、独立して、Ｈ又は−ＣＮであり、但し、少なくとも１つのＲ^７は、−ＣＮである）の化合物の同時又はその後のニトリル水素化及び還元的アミノ化を含み、
式（ＶＩＩ）の化合物は、前述の方法によって得られる。 Therefore, the present invention also relates to the formula (VI).

(In the formula, R ⁶ is independently H, or -CH _2- NH ₂ , but at least one of ^{R 6} _{is -CH 2-} NH ₂ ) for the preparation of xylene derivatives. Regarding the method of
Equation (VII)

Includes simultaneous or subsequent nitrile hydrogenation and reductive amination of the compounds (where R ⁷ is independently H or -CN, but at least one R ^{7 is -CN).} ,
The compound of formula (VII) is obtained by the method described above.

In a further embodiment of the present invention, the method starting from the compounds of formulas (I) and (III) to obtaining the compound of formula (IV) can be carried out in a single step as a one-pot reaction.

Compounds of formula (I) and formula (V) are novel intermediates useful in the methods described above. Therefore, the present invention also relates to these compounds.

The oxanorbornene derivative of formula (I) further constitutes an intermediate useful in the preparation of other chemical compounds.

In practice, the 2- or 3-cyanobenzaldehyde, or 2,3-dicyanobenzaldehyde, obtained from the oxanorbornene derivative of formula (I) is also 2-cyanobenzoic acid, 3-cyanobenzoic acid, or 2,3. -Can be converted to dicyanobenzaldehyde. The conversion of 3-cyanobenzaldehyde (also referred to as m-cyanobenzaldehyde) to 3-cyanobenzoic acid (also referred to as m-cyanobenzoic acid) is specifically described in US Pat. No. 6,262,292. And all its contents are incorporated herein by reference for all purposes. This is illustrated in Example 1.6 of the title of this patent. Using similar reaction conditions, 2-cyanobenzaldehyde (also referred to as o-cyanobenzaldehyde) or 2,3-dicyanobenzaldehyde as reagents, 2-cyanobenzoic acid (o-cyanobenzoic acid) or 2 respectively. , 3-Dicyanobenzoic acid can be obtained.

2-Cyanobenzoic acid, 3-cyanobenzoic acid, or 2,3-dicyanobenzoic acid is then converted to orthophthalic acid, isophthalic acid, or hemimeric acid (also referred to as 1,2,3-benzenetricarboxylic acid). Can be converted. The conversion of 3-isocianulic acid to isophthalic acid involves adding 3-cyanobenzoic acid to an aqueous solution of hydroxide (preferably sodium hydroxide) and then at least 10 at a temperature of at least 50 ° C (preferably at least 100 ° C). Heat for minutes (preferably at least 1 hour, more preferably at least 3 hours), then cool (preferably down to a temperature of up to 50 ° C., more preferably up to 30 ° C.), and then precipitate isophthalic acid. Thus, it can be carried out by acidifying the solution (preferably down to pH = 2 or less, more preferably down to pH = 1.5 or less). This is illustrated in Example 1.7 of the title of this patent. Orthophthalic acid or hemimeritic acid can be obtained using o-cyanobenzoic acid or 2,3-dicyanobenzoic acid as reagents, respectively, using similar reaction conditions.

Alternatively, 2-cyanobenzoic acid, 3-cyanobenzoic acid, or 2,3-dicyanobenzoic acid is then followed by 2-aminomethylbenzoic acid, 3-aminomethylbenzoic acid, or 2,3-di (aminomethyl). Can be converted to benzoic acid. The conversion of 3-aminomethylbenzoic acid to 3-aminomethylbenzoic acid is specifically described in Pamphlet 2011/161615 (particularly on page 59), the entire contents of which for all purposes. Incorporated herein by reference. This is illustrated in Example 1.8 of the title of this patent. Using similar reaction conditions, 2-aminomethylbenzoic acid or 2,3-di (aminomethyl) benzoic acid can be obtained using 2-cyanobenzoic acid or 2,3-dicyanobenzoic acid as reagents, respectively. it can.

If the disclosure of any of the patents, patent applications, and publications incorporated herein by reference conflicts with the description of the patent name to the extent that the term may be obscured, this description shall prevail.

Here, the present invention will be illustrated by the following examples, but the present invention is not intended to be limited thereto.

Ｄｅａｎ−Ｓｔａｒｋトラップ及び磁気攪拌棒を備えた二口丸底フラスコにフルフラール（１０．０ｇ、１０３ミリモル）、トルエン（４００ｍｌ）、及びエチレングリコール（４．５ｇ、７２．５ミリモル）を加えた。次いで、カンファースルホン酸（２７０ｍｇ、１．２ミリモル）を混合物に加えた。反応混合物を還流下で５時間撹拌した。次いで、混合物を室温に冷却し、ＮａＨＣＯ_３飽和水溶液（５０ｍｌ、３回）、次いで水（５０ｍｌ、３回）で洗浄した。乾燥（ＭｇＳＯ_４）した後、溶媒を蒸発させ、残渣をフラッシュクロマトグラフィー（シリカゲル、ＥｔＯＡｃ／シクロヘキサン）で精製し、８．６ｇ（８５％）のわずかに黄色の液体を得た。 Example 1
1.1 Full frill dioxolane synthesis

Furfural (10.0 g, 103 mmol), toluene (400 ml), and ethylene glycol (4.5 g, 72.5 mmol) were added to a two-necked round-bottom flask equipped with a Dean-Stark trap and a magnetic stir bar. Camphorsulfonic acid (270 mg, 1.2 mmol) was then added to the mixture. The reaction mixture was stirred under reflux for 5 hours. The mixture was then cooled to room temperature and washed with NaHCO ₃ saturated aqueous solution (50 ml, 3 times) and then water (50 ml, 3 times). After drying (ethyl ₄ ), the solvent was evaporated and the residue was purified by flash chromatography (silica gel, EtOAc / cyclohexane) to give 8.6 g (85%) of a slightly yellow liquid.

１．２ ２−（２−フリル）１，３−ジオキソランとアクリロニトリルとのディールス−アルダー反応

凝縮器及び磁気攪拌棒を備えた１００ｍｌの一口丸底フラスコに２−（２−フリル）１，３−ジオキソラン（１９．８０ｇ、１３８．５ミリモル）を秤量した。次いで、アクリロニトリル（４０．０ｇ、７４６ミリモル）及びＺｎＣｌ_２（２．０ｇ、１４．４ミリモル）を加えた。反応混合物を６０℃で２４時間撹拌した。付加物における変換率が９０％、選択性が９３％である１−（１，３−ジオキソラン−２−イル）−７−オキサビシクロ［２．２．１］ヘプト−５−エン−２−カルボニトリル及び４−（１，３−ジオキソラン−２−イル）−７−オキサビシクロ［２．２．１］ヘプト−５−エン−２−カルボニトリル）。 1 H-NMR (400 MHz, DMSO):

1.2 Diels-Alder reaction of 2- (2-frill) 1,3-dioxolane with acrylonitrile

2- (2-Frill) 1,3-dioxolane (19.80 g, 138.5 mmol) was weighed into a 100 ml round bottom flask equipped with a condenser and a magnetic stir bar. Acrylonitrile (40.0 g, 746 mmol) and ZnCl ₂ (2.0 g, 14.4 mmol) were then added. The reaction mixture was stirred at 60 ° C. for 24 hours. 1- (1,3-dioxolane-2-yl) -7-oxabicyclo [2.2.1] hept-5-en-2-carbo with 90% conversion and 93% selectivity in the adduct Nitriles and 4- (1,3-dioxolane-2-yl) -7-oxabicyclo [2.2.1] hept-5-en-2-carbonitrile).

The reaction mixture was concentrated under reduced pressure to give 27 g of dark black oil. The crude product was purified by flash chromatography (silica gel, EtOAc / Cyclohexane) to give 11.7 g of the expected end adduct and 7 g of the expected exo adduct as a slightly yellow oil overall. The isolated yield is 70%. Under these conditions, the subdivision of different isomers is ortho / meta 52/48% and endo / exo 66/33%.

１．３ 上記実施例のディールス−アルダー付加物の２−（１，３−ジオキソラン−２−イル）ベンゾニトリル及び３−（１，３−ジオキソラン−２−イル）ベンゾニトリルへの変換

ＰＴＦＥセプタムスクリューキャップを取り付けたカルーセルチューブにエンド付加物（１．０ｇ、５．２ミリモル）、ジメチルスルホキシド（７．５ｍｌ）、及びナトリウムメトキシド溶液（メタノール中２５重量％、２２５ｍｇ、１．０ミリモル）を入れた。反応混合物を１００℃で１時間撹拌した。冷却後、粗生成物をジクロロメタン（２０ｍｌ）で希釈した。混合物を水（１０ｍｌ）で洗浄した。水相をジクロロメタン（２０ｍｌ）で抽出し、有機相を水（１０ｍｌ、３回）で洗浄した。乾燥（ＭｇＳＯ４）した後、溶媒を蒸発させて８４０ｍｇの油状液体（９３％）を得た。メタにおけるニトリル基の僅かな加水分解は、こうした条件で観察することができる。 1 H-NMR (400 MHz, DMSO):

1.3 Conversion of the Diels-Alder adduct of the above example to 2- (1,3-dioxolan-2-yl) benzonitrile and 3- (1,3-dioxolan-2-yl) benzonitrile

Endoadduct (1.0 g, 5.2 mmol), dimethyl sulfoxide (7.5 ml), and sodium methoxide solution (25 wt% in methanol, 225 mg, 1.0 mmol) in a carousel tube fitted with a PTFE septum screw cap. ) Was put in. The reaction mixture was stirred at 100 ° C. for 1 hour. After cooling, the crude product was diluted with dichloromethane (20 ml). The mixture was washed with water (10 ml). The aqueous phase was extracted with dichloromethane (20 ml) and the organic phase was washed with water (10 ml, 3 times). After drying (sulfonyl4), the solvent was evaporated to give 840 mg of oily liquid (93%). The slight hydrolysis of nitrile groups in the meta can be observed under these conditions.

１．４ ２−ホルミルベンゾニトリル及び３−ホルミルベンゾニトリルに対する２−（１，３−ジオキソラン−２−イル）ベンゾニトリル及び３−（１，３−ジオキソラン−２−イル）ベンゾニトリルの脱保護
ＴＨＦ（１０ｍｌ）に溶解した２−及び３−（１，３−ジオキソラン−２−イル）ベンゾニトリル（２００ｍｇ、１．１４ミリモル）の撹拌溶液に室温で１Ｎ塩酸溶液（１０ｍｌ）を加えた。混合物を８０℃で１時間加熱し、室温に冷却した。反応混合物をクロロホルム（１０ｍｌ、３回）で抽出した。合わせたクロロホルム溶液を乾燥させ（無水ＭｇＳＯ４）、濾過し、減圧下で蒸発させて、１４７ｍｇ（９８％）の２−ホルミルベンゾニトリル及び３−ホルミルベンゾニトリルを得た。 1 H-NMR (400 MHz, DMSO):

1.4 Deprotection of 2- (1,3-dioxolan-2-yl) benzonitrile and 3- (1,3-dioxolan-2-yl) benzonitrile against 2-formylbenzonitrile and 3-formylbenzonitrile THF A 1N hydrochloric acid solution (10 ml) was added to a stirred solution of 2- and 3- (1,3-dioxolane-2-yl) benzonitrile (200 mg, 1.14 mmol) dissolved in (10 ml) at room temperature. The mixture was heated at 80 ° C. for 1 hour and cooled to room temperature. The reaction mixture was extracted with chloroform (10 ml, 3 times). The combined chloroform solutions were dried (anhydrous sulfonyl4), filtered and evaporated under reduced pressure to give 147 mg (98%) of 2-formylbenzonitrile and 3-formylbenzonitrile.

１．５ １，３−フェニレンジメタンアミンへの３−ホルミルベンゾニトリルの変換
メタノールに溶解した１１３ｇのＮＨ３（７モル／ｌ、ｄ＝０．７７９）、０．７ｇのＲａｎｅｙ Ｃｏ、及び７ｇの３−ホルミルベンゾニトリルを含むバッチ式反応器で同時水素化及び還元的アミノ化を実行し、ＮＨ３／芳香族の比は、１００℃、５時間、５０バールの水素で約１９である。収率はメタキシレンジアミンで定量的であった。 1 H-NMR (400 MHz, DMSO):

1.5 Conversion of 3-formylbenzonitrile to 1,3-phenylenedimethaneamine 113 g of NH3 (7 mol / l, d = 0.779) dissolved in methanol, 0.7 g of Raney Co, and 7 g of Simultaneous hydrogenation and reductive amination were performed in a batch reactor containing 3-formylbenzonitrile, with an NH3 / aromatic ratio of about 19 at 100 ° C. for 5 hours at 50 bar hydrogen. The yield was quantitative with m-xylylenediamine.

１．６ ｍ−シアノベンズアルデヒド（３−ホルミルベンゾニトリル）のｍ−シアノ安息香酸への変換

２６．２ｇのｍ−シアノベンズアルデヒド、４０ｇのジオキサン、１７．６ｇの炭酸水素ナトリウム、及び１００ｇの水を攪拌しながら混合する。反応系の内温を５０℃以下に保ちながら、ｐＨ９に調整した１３．５重量％の次亜塩素酸ナトリウム水溶液２１０ｇを１時間にわたり滴下し、得られた混合物を更に１時間攪拌する。次いで、３．６ｇの尿素を加え、得られた混合物を２０分間撹拌する。更に、１２ｇの９８重量％硫酸及び３００ｇの水を加える。沈殿した結晶が形成され、これを濾過し、水で洗浄し、乾燥させて約２７ｇ（収率：約９２％）のｍ−シアノ安息香酸を得た。純度は９８％以上である。 1 H-NMR (400 MHz, DMSO):

1.6 Conversion of m-cyanobenzaldehyde (3-formylbenzonitrile) to m-cyanobenzoic acid

Mix 26.2 g of m-cyanobenzaldehyde, 40 g of dioxane, 17.6 g of sodium bicarbonate, and 100 g of water with stirring. While keeping the internal temperature of the reaction system at 50 ° C. or lower, 210 g of a 13.5% by weight sodium hypochlorite aqueous solution adjusted to pH 9 is added dropwise over 1 hour, and the obtained mixture is stirred for another 1 hour. Then 3.6 g of urea is added and the resulting mixture is stirred for 20 minutes. Further, 12 g of 98 wt% sulfuric acid and 300 g of water are added. Precipitated crystals were formed, which were filtered, washed with water and dried to give about 27 g (yield: about 92%) of m-cyanobenzoic acid. The purity is 98% or more.

水（２６ｇ）に溶解した水酸化ナトリウム（２．９３ｇ）の溶液に５．０ｇの３−シアノ安息香酸（ｍ−シアノ安息香酸）を加えた。得られた溶液を５時間加熱し還流（１１５℃）した。冷却後、７０ｍｌの水を加え、９５％硫酸を滴下して加えて溶液をｐＨ＝１に酸性化した。白色の固体沈殿物が形成した。白色の固体沈殿物を濾過し、１０ｍｌの水で３回洗浄した。乾燥後（６０℃、１０ミリバール、２時間）、５．４４ｇのイソフタル酸（収率９６％）を得た。 Conversion of 1.7 m-cyanobenzoic acid to isophthalic acid

5.0 g of 3-cyanobenzoic acid (m-cyanobenzoic acid) was added to a solution of sodium hydroxide (2.93 g) dissolved in water (26 g). The resulting solution was heated for 5 hours and refluxed (115 ° C.). After cooling, 70 ml of water was added, 95% sulfuric acid was added dropwise, and the solution was acidified to pH = 1. A white solid precipitate formed. The white solid precipitate was filtered and washed 3 times with 10 ml of water. After drying (60 ° C., 10 mbar), 5.44 g of isophthalic acid (yield 96%) was obtained.

メタノール（２０ｍｌ）に溶解した３−シアノ安息香酸（２ｇ、１３．５９ミリモル）の溶液に０℃でラネーニッケル（０．４ｇ）を加え、室温で１時間、Ｈ_２バルーンを用いて水素雰囲気下に保つ。完了後、反応混合物を、メタノールにおける予め洗浄したセライト（登録商標）パッドに通して濾過し、メタノールで洗浄する。溶媒を真空下で蒸発させて、表題の化合物を無色のシロップとして得る。約２ｇの３−アミノメチル安息香酸が得られる。 1.8 Conversion of isophthalic acid to 3-aminomethylbenzoic acid

It was dissolved in methanol (20 ml) 3- cyanobenzoic acid (2 g, 13.59 mmol) Raney Nickel (0.4 g) was added at 0 ℃ to a solution of 1 hour at room temperature under a hydrogen atmosphere using a balloon _{of H 2} keep. Upon completion, the reaction mixture is filtered through a pre-washed Celite® pad in methanol and washed with methanol. The solvent is evaporated under vacuum to give the title compound as a colorless syrup. About 2 g of 3-aminomethylbenzoic acid is obtained.

Example 2
Similar to Example 1.2, Diels-Alder (DA) condensation with acrylonitrile was performed using various furfural derivatives to determine the various isomers obtained. The results are summarized in Table 1 below.

Comparative Example 1
The above-mentioned Example 1 was repeated using 1 equivalent of furfural instead of furfural ethylene glycol ketal. The results are summarized in Table 2 below.

No reaction between furfural and acrylonitrile was observed under any of the conditions summarized in the table above.

Comparative Example 2
Example 1 was repeated with 1 equivalent of furfural diethyl ketal instead of furfural ethylene glycol ketal. The results are summarized in Table 3 below.

No reaction between furfural diethyl ketal and acrylonitrile was observed under any of the reaction conditions summarized in the table above.

ＰＴＦＥセプタムスクリューキャップが取り付けられたカルーセルチューブで、２−（２−フリル）１．３−ジオキソラン（０．５ｇ、３．６ミリモル）を秤量した。次いで、アリルアミン（１．０２ｇ、１７．９ミリモル）及びＺｎＣｌ_２（１９５ｍｇ、０．７ミリモル）を加えた。反応混合物を６０℃で１８時間撹拌した。反応を^１ＨＮＭＲ分光法によってモニターした。 Comparative Example 3

2- (2-Frill) 1.3-dioxolane (0.5 g, 3.6 mmol) was weighed in a carousel tube fitted with a PTFE septum screw cap. Then allylamine (1.02 g, 17.9 mmol) and ZnCl ₂ (195 mg, 0.7 mmol) were added. The reaction mixture was stirred at 60 ° C. for 18 hours. The reaction was monitored by ^{1 1 HNMR spectroscopy.}

No reaction was observed after stirring at 60 ° C. for 18 hours.

Claims (12)

Equation (I)

(During the ceremony
X and Y are O, or X and Y are S.
R _{is, -CH 2 -CH 2 -, -} CH 2 -CH 2 -CH 2 -, - CH (CH 3) -CH (CH 3) -, or _{-CH 2 -C (CH 3) 2} -CH 2 - and,
R ² is independently H, alkyl, alkenyl, or aryl, and R ³ and R ⁴ are independently H or -CN, provided that at least one of ^{R 3} and R ^{4 is.} , -CN, and R ⁵ is R ² , -CH ₂ OR ² , -CO ₂ R ² , or

Is a method for the preparation of the compound of formula (II).

Compounds of the formula (where X, Y, R, R ² and R ⁵ are defined as described above) are compounded in formula (III) or (III').

A method comprising reacting with a compound (in the formula, R ³ and R ⁴ are defined as described above). X and Y are O, and The method of claim 1. The method according to claim 1 or 2 , wherein R ^{2 is H.} Equation (IV)

(During the ceremony
X is defined as described below and
R ² is independently H, alkyl, alkenyl, or aryl,
R ³ and R ⁴ are independently H or -CN, except that at least one of ^{R 3} and R ^{4 is -CN.}
R ⁵ is R ² , -CH ₂ OR ² , -CO ₂ R ² , or

And
In the formula, Y is defined as described below .
R _{is, -CH 2 -CH 2 -, -} CH 2 -CH 2 -CH 2 -, - CH (CH 3) -CH (CH 3) -, or _{-CH 2 -C (CH 3) 2} -CH 2 - ), A method for the preparation of compounds
a) Equation (I)

(In the formula, X and Y are O, or X and Y are S, and R, R ² , R ³ , R ⁴ , and R ⁵ are defined as described above). Is dehydrated / aromaticized to formula (V)

Obtaining a compound of the formula (where X, Y, R, R ² , R ³ , R ⁴ and R ⁵ are defined as described above) and then deprotecting the compound of formula (V). Or b) a method comprising performing the dehydration / aromatization and deprotection of the compound of formula (I) in a single step. X and Y are O, and The method of claim 4. The method according to claim 4 or 5 , wherein R ² is H. The method according to any one of claims 4 to 6 , wherein the compound of the formula (I) is obtained by the method according to any one of claims 1 to 3 . Equation (VI)

(In the formula, R ⁶ is independently H, or -CH _2- NH ₂ , but at least one of ^{R 6} _{is -CH 2-} NH ₂ ) for the preparation of xylene derivatives. Method, formula (VII)

Simultaneous or subsequent simultaneous or subsequent nitrile hydrogenation and reductive amination of the compounds (where R ⁷ is independently H or -CN, but ^{at least one of R 7 is -CN).} The method, wherein the compound of formula (VII) is obtained by the method according to any one of claims 5-7. Equation (I)

( During the ceremony
X and Y are O, or X and Y are S.
R _{is, -CH 2 -CH 2 -, -} CH 2 -CH 2 -CH 2 -, - CH (CH 3) -CH (CH 3) -, or _{-CH 2 -C (CH 3) 2} -CH 2 - and,
R ² is independently H, alkyl, alkenyl, or aryl,
R ³ and R ⁴ are independently H or -CN, except that ^{at least one of R 3} and R ⁴ is -CN, and R ⁵ is R ² , -CH ₂ OR ² , -CO ₂ R ² or

However, 7-oxabicyclo [2.2.1] hept-5-en-2-carbonitrile, l- (1,3-dithiolane-2-yl) -5- Compounds excluding methyl- . X and Y are O, and A compound according to claim 9. R ² is H, A compound according to claim 9 or 10. Meta-xylene diamine, ortho-xylene diamine, 1,2,3-tri (aminomethyl) benzene, 3-cyanobenzoic acid, 2-cyanobenzoic acid, 2,3-dicyanobenzoic acid, isophthalic acid, orthophthalic acid, hemi 9. to 11 for the production of a xylene derivative selected from the group consisting of merit acid, 3-aminomethylbenzoic acid, 2-aminomethylbenzoic acid, and 2,3-di (aminomethyl) benzoic acid . Use of the compound according to any one of the following items.